BT1549 coordinates the in vitro IL-10 inducing activity of Bacteroides thetaiotaomicron.

The intestine is home to a complex immune system that is engaged in mutualistic interactions with the microbiome that maintain intestinal homeostasis. A variety of immune-derived anti-inflammatory mediators have been uncovered and shown to be critical for maintaining these beneficial immune-microbiome relationships. Notably, the gut microbiome actively invokes the induction of anti-inflammatory pathways that limit the development of microbiome-targeted inflammatory immune responses. Despite the importance of this microbiome-driven immunomodulation, detailed knowledge of the microbial factors that promote these responses remains limited. We have previously established that the gut symbiont Bacteroides thetaiotaomicron stimulates the production of the anti-inflammatory cytokine IL-10 via soluble factors in a Toll-like receptor 2 (TLR2)-MyD88-dependent manner. Here, using TLR2 activity reporter cell lines, we show that the capacity of B. thetaiotaomicron to stimulate TLR2 activity was not critically dependent on either of the canonical heterodimeric forms of TLR2, TLR2/TLR1, or TLR2/TLR6, that typically mediate its function. Furthermore, biochemical manipulation of B. thetaiotaomicron-conditioned media suggests that IL-10 induction is mediated by a protease-resistant or non-proteogenic factor. We next uncovered that deletion of gene BT1549, a predicted secreted lipoprotein, significantly impaired the capacity of B. thetaiotaomicron to induce IL-10, while complementation in trans restored IL-10 induction, suggesting a role for BT1549 in the immunomodulatory function of B. thetaiotaomicron. Collectively, these data provide molecular insight into the pathways through which B. thetaiotaomicron operates to promote intestinal immune tolerance and symbiosis. Intestinal homeostasis requires the establishment of peaceful interactions between the gut microbiome and the intestinal immune system. Members of the gut microbiome, like the symbiont Bacteroides thetaiotaomicron, actively induce anti-inflammatory immune responses to maintain mutualistic relationships with the host. Despite the importance of such interactions, the specific microbial factors responsible remain largely unknown. Here, we show that B. thetaiotaomicron, which stimulates Toll-like receptor 2 (TLR2) to drive IL-10 production, can stimulate TLR2 independently of TLR1 or TLR6, the two known TLR that can form heterodimers with TLR2 to mediate TLR2-dependent responses. Furthermore, we show that IL-10 induction is likely mediated by a protease-resistant or non-proteogenic factor, and that this requires gene BT1549, a predicted secreted lipoprotein and peptidase. Collectively, our work provides insight into the molecular dialog through which B. thetaiotaomicron coordinates anti-inflammatory immune responses. This knowledge may facilitate future strategies to promote such responses for therapeutic purposes.

Citation

Morgan J Engelhart, Orion D Brock, Jessica M Till, Robert W P Glowacki, Jason W Cantwell, David J Clarke, Darryl A Wesener, Philip P Ahern. BT1549 coordinates the in vitro IL-10 inducing activity of Bacteroides thetaiotaomicron. Microbiology spectrum. 2025 Mar 04;13(3):e0166924

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PMID: 39868786

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